Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine: Role of BDNF-TrkB signaling

Publication date: Available online 19 December 2019Source: Pharmacology Biochemistry and BehaviorAuthor(s): Yunfei Tan, Yuko Fujita, Youge Qu, Lijia Chang, Yaoyu Pu, Siming Wang, Xingming Wang, Kenji HashimotoAbstractThe N-methyl-d-aspartate receptor (NMDAR) antagonists including phencyclidine (PCP) and ketamine produce cognitive deficits in rodents and humans. We previously reported that (R)-ketamine produced the beneficial effects compared to (S)-ketamine in several animal models including depression. Here we compared the effects of two enantiomers of ketamine on cognitive deficits in mice after repeated administration of PCP. PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were ameliorated by subsequent repeated intermittent administration of (R)-ketamine (10 mg/kg/day, twice weekly for 2-weeks), but not (S)-ketamine. Western blot analysis showed decreased levels of brain-derived neurotrophic factor (BDNF) and decreased ratio of phosphorylated-TrkB (p-TrkB) to TrkB in the prefrontal cortex (PFC) and hippocampus of PCP-treated mice. Furthermore, PCP-induced reduction of BDNF and p-TrkB/TrkB ratio in the PFC and hippocampus of PCP-treated mice was ameliorated by subsequent intermittent administration of (R)-ketamine. Interestingly, the beneficial effects of (R)-ketamine were blocked by pretreatment with TrkB inhibitor ANA-12. These findings suggest that (R)-ketamine could ameliorate PCP-induced cognitive deficits via activation of BDNF-TrkB signaling in the b...
Source: Pharmacology Biochemistry and Behavior - Category: Biochemistry Source Type: research